- Structure and interactions of ribonucleoprotein complexes involved in translation control
- Aberrant translation control in neurodegeneration
- Host-pathogen interactions in translation control
- Provide mechanistic understanding including target recognition and molecular interactions of translation control processes.
- Define working principles of RQC components and their disease-causing mutations in neurons.
- Reveal the molecular mechanisms by which viruses affect host translation control.
Content of research
Translation control and neurodegeneration
Translation control pathways have evolved in all domains of life to prevent damage caused by truncated nascent proteins and aberrant mRNAs. Co-translational quality control is triggered by persistent translation stalling leading to ribosomal collisions. Here, collided ribosomes act as a proxy of translation problems. Persistently collided ribosomes initiates a range of cellular response pathways from Ribosome-associated Quality Control (RQC) and mRNA decay to stress response patwhays and potentially even apoptosis. Ribosome-associated quality control is crucial for degrading truncated nascent proteins produced on aberrant mRNAs. Mutations in RQC components cause neurodegeneration both in animal models and human patients. Moreover, RQC insufficiency and subsequent protein aggregation critically contribute to proteostasis impairment and systemic decline during ageing. Strikingly, we still lack mechanistic understanding of many steps in this crucial process. Our approach utilizes a multidisciplinary approach to provide detailed mechanistic understanding of the critical RQC system in combination with an in vivo study to reveal processes leading to RQC-driven pathological changes in neural tissue. Since the RQC pathway is conserved in all kingdoms of life and serves a pivotal role in protein homeostasis with critical implications for neurodegenerative disorders and ageing, our findings will have important implications for human health and the potential to reveal novel drug targets.
Translation in the context of human host-pathogen interactions
Translation is also critical in the context of human host-pathogen interaction where the ribosome, as the central molecular machine for genetic information expression, is the subject to numerous regulatory and quality control events and pathological interventions. To ensure the translation of their own mRNAs, viruses take control of the host protein synthesis machinery, effectively recruiting ribosomes to work on viral mRNA. Conversely, the host's intrinsic immune defenses often target translation to disable the infected cell's protein synthesis apparatus. The strategies adopted by viruses to reprogram translation and co-translational quality control machinery to promote infection are poorly understood. Thus, there is an urgent need for further research in this area to develop effective strategies for combating viral infections. To address this knowledge gap, we will elucidate the mechanistic details of viral reprogramming of translation and translational control processes using biochemical and structural techniques. By elucidating the mechanistic details behind viral manipulation of these processes at a molecular level, we can lay the foundation for developing effective strategies against viral infections.